This multidisciplinary program involves well-established and productive experts in nanotechnology and tendon-to-bone testing, analysis, and surgical application from Washington University's Departments of Biomedical Engineering and Orthopaedic Surgery. Our goal is to design, fabricate, and validate novel nanostructures for use in the surgical repair of rotator cuff tears to restore the torn tendon to its bony insertion. We will take a biomimetic approach to this problem by applying knowledge of the natural tendon-to-bone insertion to design and fabricate novel nanofiber scaffolds from a biodegradable polymer by electrospinning, followed by coating with calcium phosphate in a continuous gradation. The scaffolds will be combined with mesenchymal stem cells (MSCs) and implanted in our well-established rat rotator cuff injury-and-repair model to enhance tendon- to-bone healing. The scaffolds we will develop have gradations in mineral content to mimic the natural insertion site, and can serve as grafts to guide tissue regeneration in vivo for tendon-to-bone healing. Our long-term objective is that these scaffolds will be used in a clinical setting for successful repair of soft tissue (meniscus-, ligament-, and cartilage-) to bone interface. The scope of this research includes: i) Fabricating nanofiber scaffolds with different structural orders and continuous gradations in mineral content by a combination of electrospinning and biomineralization;ii) testing and then optimizing the mechanical properties of the graded scaffolds for use in tendon-to-bone repair;iii) examining and quantifying the cellular response to a graded scaffold;and iv) determining the effect of a mineral gradient and seeding of MSCs on tendon-to-bone healing. PUBLIC HEALTH RELEVANCE: We will design, fabricate, and validate a novel class of scaffolds based on electrospun nanofibers and with continuous gradations in mineral content for rotator cuff repair - that is, surgical reattachment of the torn tendons to their bony insertions. It is a clinically significant problem that affects approximately 30% of the population over the age of 60. The current failure rates range from 30% to 94%. Reducing these failure rates will have a major impact on shoulder function in these patients. This research will improve the health and quality of life for individuals afflicted with rotator cuff injuries, having significant impact on the treatment of diseases at rotator cuff and other soft tissue-to-bone interfaces (e.g., anterior cruciate ligament reconstruction).